Metabolic syndrome is the collective presence of symptoms related to insulin resistance, glucose intolerance, dyslipidemia, high cholesterol, hypertension, and abdominal obesity. These symptoms, when present in different combinations and different levels, increase the risk of cardiovascular diseases. Metabolic syndrome related symptoms are also good indicators of prediabetic conditions in individuals.
To determine the presence of metabolic syndrome in individuals, physicians can use more than one definition, like one put forth by the World Health Organization (“WHO”) or by the Adult Treatment Panel III (“ATP-III”), or by the International Diabetes Federation. The diagnosis is based on the presence of a combination of metabolic disorders. For example, according to WHO, a person should have glucose intolerance or diabetes and two of the following three disorders: waist to hip ratio>0.9, BMI>30 or triacylglycerols>150 mg/dl or blood pressure>140/90 mm of Hg or albumin to creatine ratio of 30 mg/g. Using the most recent and well-accepted definition provided by the ATP-III (≧3 of the following abnormalities), metabolic syndrome is defined as: waist circumference greater than 102 cm in men and 88 cm in women; serum triglyceride levels of at least 150 mg/dl; high density lipoprotein cholesterol level of less than 40 mg/dl in men and 50 mg/dl in women; blood pressure of at least 130/85 mm of Hg; or serum glucose level of at least 110 mg/dl.
Since the condition is a combination of various components, symptoms or disorders, the diagnosis is not absolute and would be expected to differ depending on the definition used, the dynamics of the population and the physicians conducting the diagnosis. Due to the lack of a standardized set of criteria, it is difficult to understand the prevalence of metabolic syndrome. The overall prevalence of metabolic syndrome in U.S. adults is 20-24%. There is an upward trend of the prevalence of metabolic syndrome with increasing age. The prevalence is 7% in the 20 to 29 age group and as high as 40-45% in the 60 to 69 and over 70 yrs age group. African-American women have a 57% higher prevalence rate then African-American men. Using 2000 census data, about 47 million U.S. residents have the metabolic syndrome (Cook et al, 2008 and Ford et al, 2002). Prevalence outside the U.S. has been observed at 15% in Europe, 7% in Korea, 30% in Iran and 32% in India.
Metabolic Syndrome—Disease Components, Symptoms and Risk Factors
Diabetes and Prediabetes
Diabetes is both a component and effect of metabolic syndrome. There are several different classifications of diabetes. For example, type 1 diabetes results from the body's failure to produce insulin, the hormone responsible for metabolism of sugar. It is estimated that 5-10% of Americans who are diagnosed with diabetes have type 1 diabetes. Gestational diabetes affects about 4% of all pregnant women, or approximately 135,000 cases in the United States each year.
Type 2 diabetes results from insulin resistance (a condition in which the body fails to properly use insulin), combined with relative insulin deficiency. Most Americans who are diagnosed with diabetes have type 2 diabetes. Of the key types of diabetes, type 2 is most frequently spotlighted because it is essentially preventable. This disease is deemed largely preventable by the medical community because it is understood to be a result of a lifestyle fraught with poor dietary habits, infrequent or no exercise, and other factors.
Pre-diabetes is a condition that occurs when a person's blood glucose levels are higher than normal but not high enough for a diagnosis of type 2 diabetes. There are 41 million Americans who have pre-diabetes, in addition to the 20.8 million with diabetes. For the 41 million Americans suffering from pre-diabetes—a precursor to diabetes type 2—the American Diabetes Association (ADA) recommends lifestyle modifications, including dietary supplementation, to treat the condition and alleviate its adverse effects.
Pre-diabetes is a more recently used term to describe the state of elevated blood glucose levels. It is more formally known as “impaired glucose tolerance” or “impaired fasting glucose,” depending on which test is used to ascertain the condition. According to the ADA, the condition of pre-diabetes “almost always” exists prior to the full development of type 2 diabetes. Research has also shown that if a person takes action to manage his or her blood glucose when he or she has pre-diabetes, the individual can delay or prevent type 2 diabetes from ever developing.
In summary, a lifestyle of high sugar intake is a major risk factor for the development of pre-diabetic and type 2 diabetic states. The rise of industrialization has, for many Americans, wiped out the ability of attaining nature-based whole foods from the land, which the evolution of the human body has come to rely on to maintain homeostasis. As more sugar-laden processed and packaged (i.e., “convenient”) foods displaced the wholesome diet, cases of type 2 diabetes began to increase sharply.
Insulin and Insulin Resistance
After a meal, the body's master metabolic hormone—insulin—is released from the pancreas into the bloodstream to transport the glucose from the bloodstream into cells that rely on the glucose for energy. In cases where the bloodstream is repeatedly inundated with glucose, the body's pancreatic cells release high levels of insulin to clear the glucose by cellular uptake. Inside the cell, glucose is either used for energy or stored for future use in the form of glycogen. However, insulin can lose its effectiveness over time, thereby leaving behind more glucose in the bloodstream.
“Glycemic response” is the pathway by which glucose reacts with insulin. Many foods contain carbohydrates that are broken down to glucose and rapidly absorbed from the intestine into the bloodstream. This rapid absorption of glucose leads to a high glycemic response or glycemic index (GI) and a consequent rapid secretion of insulin from the pancreas. Increased insulin levels are thought to be a key factor in the development of several diseases, including non-insulin dependent diabetes, cardiovascular disease, metabolic syndrome (Syndrome X), and insulin resistance.
Insulin resistance occurs when the normal amount of insulin secreted by the pancreas is unable to effectively mediate glucose uptake. To compensate, the pancreas secretes additional insulin. When the body's cells resist or do not respond to even high levels of insulin, glucose builds up in the blood resulting in high blood sugar. Even individuals being treated with oral medication or insulin injections to control their blood glucose levels can have higher than normal blood insulin levels due to insulin resistance.
More and more people in the United States are becoming obese, physically inactive, or both. Obesity and physical inactivity aggravate insulin resistance. Also, people who are insulin resistant typically have an imbalance in their blood lipids. They have an increased level of triglycerides (fat) and a decreased level of HDL (“good”) cholesterol. Imbalances in total fat and HDL cholesterol increase the risk for heart disease. These findings have heightened awareness of insulin resistance and its impact on health.
Almost all individuals with type 2 diabetes mellitus (“diabetes”)—and many with hypertension, cardiovascular disease, and obesity—are insulin resistant. These diseases and conditions have been predominantly found in highly industrialized countries with improved economic status, such as the United States. However, the prevalence of high sugar/high calorie foods has spread these diseases to rapidly developing economies like India and China. In the United States, these diseases and conditions are among the leading contributors to morbidity and mortality. Approximately 20-25% of the “healthy” population may be insulin resistant.
There are no outward physical signs of insulin resistance. A glucose tolerance test, during which insulin and blood glucose are measured, can help determine if someone is insulin resistant. There are also two different tests medical personnel may use to determine whether an individual has pre-diabetes: the fasting plasma glucose test (FPG) or the oral glucose tolerance test (OGTT). The blood glucose levels measured after these tests determine whether the individual has a normal metabolism, or whether the individual has pre-diabetes or diabetes. If an individual's blood glucose level is abnormal following the FPG, the individual has impaired fasting glucose (IFG). If an individual's blood glucose level is abnormal following the OGTT, the individual has impaired glucose tolerance (IGT).
Body Mass Index (BMI) and Waist to Hip Ratio
Body mass index is one measurement that factors in obesity as a marker for metabolic syndrome. However, due to the variability in the overall distribution of excess fat in the body, and the associated risk of cardiovascular diseases depending upon body type, ethnicity, regional variations, eating habits, etc., BMI was found to be insufficient to completely define the presence of metabolic syndrome. Therefore, to encompass a larger population with different body types and risks for metabolic syndrome, the waist to hip ratio was introduced as a more clinically relevant indicator.
A waist to hip ratio of >0.9 in men and >0.85 in women, a BMI of >30, or a combination of both are used as the basis to diagnose metabolic syndrome. Waist circumference is directly related to all-cause mortality when adjusted for BMI, highlighting the importance of waist to hip ratio.
Dyslipidemia
High levels of plasma triacylglycerols are considered as a significant risk factor for diagnosis of metabolic syndrome. Equally important is the levels of LDL and HDL. Low levels of plasma HDL and high levels of plasma LDL are more important for a positive diagnosis of metabolic syndrome. More specifically, the presence of small, dense LDL and triacylglycerol-rich remnant proteins is a clear indication of added risk factors for cardiovascular diseases.
High plasma triacylglycerol levels and insulin resistance have been found to co-exist in non-diabetic or prediabetic individuals, indicating some link between insulin resistance and dyslipidemia. Even in the wide range of plasma triacylglycerol levels (59-546 mg/dl) found in healthy individuals, there is a direct co-relation between increased secretion of hepatic VLDL-triacylglycerols, insulin resistance and the resultant hyperinsulinemia, clearly indicating the strong link between dyslipidemia and hepatic malfunction.
A lipoprotein profile with low levels of HDL and high levels of LDL (and more specifically high levels of VLDL) is a typical atherogenic lipoprotein profile indicating a high risk of atherosclerosis. Considering the link between plasma triacylglycerol and insulin resistance, the combined existence of these factors increases the risk of cardiovascular diseases and metabolic syndrome.
Hypertension
Another important risk factor related to metabolic syndrome is high blood pressure or hypertension. Hypertension is a chronic medical condition that may be classified as either primary (no underlying medical cause) or secondary (high blood pressure resulting from another condition). The prevalence of hypertension has reached epidemic proportions. It is estimated that 43 million people in the United States have hypertension or are taking antihypertensive medication, which is almost 24% of the adult population. Persistent hypertension is one of the risk factors for strokes, heart attacks, heart failure and arterial aneurysm, and is a leading cause of chronic renal failure. Even moderate elevation of arterial blood pressure leads to shortened life expectancy.
There is a complicated connection between hypertension and metabolic syndrome. As many as one-third of patients suffering from hypertension have metabolic syndrome, as defined by the ATP-III criteria. Hypertensive patients with metabolic syndrome exhibit an increased prevalence of hypertension-induced organ damage, left ventricular hypertrophy and atherosclerosis compared to patients with hypertension alone. The presence of both conditions results in a worsened long-term prognosis and heightened risk of cardiovascular and all-cause death.
Metabolic Syndrome—Treatments
The insulin resistance and pre-diabetes associated with metabolic syndrome can develop into type-2 diabetes. Once type-2 diabetes develops, it continues to progress despite added efforts to maintain plasma glucose levels as low as possible. Therefore, early diagnosis and treatment of metabolic syndrome is extremely important. It is equally as important to prevent the development of core metabolic syndrome and its related disorders.
Traditional approaches have focused mostly on the prevention or treatment of individual of metabolic syndrome-related components, disorders or symptoms (e.g., insulin resistance, hypertension or high plasma lipid profile, obesity, etc.) rather than treatment of the underlying syndrome itself. Pharmocologic intervention for prevention or treatment of metabolic syndrome-related disorders includes insulin secretogougues like tolbutamide, sulfonylureas, metformin, etc.; glucose uptake enzyme inhibitors like acarbose, and drugs which affect insulin sensitivity like troglitazone, etc.
Alpha-glucosidase inhibitors are oral anti-diabetic drugs that work by preventing the digestion of complex carbohydrates (such as starch). Complex carbohydrates are normally converted into simple sugars (monosaccharides) which can be absorbed through the intestine. Alpha-glucosidase inhibitors are saccharides that act as competitive inhibitors of enzymes needed to digest the carbohydrates; specifically alpha-glucosidase enzymes in the brush border of the small intestines. Hence, alpha-glucosidase inhibitors reduce the impact of complex carbohydrates on blood sugar. They are used to establish greater glycemic control over hyperglycemia in type-2 diabetes, particularly with regard to postprandial hyperglycemia. They may be used as mono-therapy in conjunction with an appropriate diabetic diet and exercise, or they may be used in conjunction with other anti-diabetic drugs. Examples of alpha-glucosidase inhibitors include the drugs Acarbose, Miglitol, and Voglibose
Inhibition of these enzyme systems reduces the rate of digestion of complex carbohydrates. Less glucose is absorbed because the carbohydrates are not broken down into glucose molecules. In diabetic individuals, the short-term effect of these drug therapies is to decrease current blood glucose levels. However, a long term effect is a small reduction in hemoglobin (A1C) level.
There are a number of difficulties associated with the use of alpha-glucosidase inhibitors. Since alpha-glucosidase inhibitors are competitive inhibitors of the digestive enzymes, they must be taken at the start of main meals to have maximal effect. Therefore, their effects on blood sugar levels require strict compliance with a dosing schedule. Because alpha-glucosidase inhibitors prevent the degradation of complex carbohydrates into glucose, the carbohydrates will remain in the intestine. In the colon, bacteria will digest the complex carbohydrates, thereby causing gastrointestinal side effects such as flatulence and diarrhea.
Alpha-amylase enzyme inhibitors are also used in the treatment of metabolic syndrome-related disorders. Alpha-amylase is a digestive enzyme that acts in the lumen of the small intestine to breakdown starch (complex carbohydrates) into smaller carbohydrate units that can subsequently be broken down into the simple sugar glucose. Glucose is absorbed directly into the bloodstream following its uptake by intestinal cells, resulting in a relatively rapid rise in serum glucose levels. Glucose is used by all cells of the body to fuel metabolism. Excess glucose, however, can be converted into fat and stored in adipose tissue.
Alpha-amylase inhibitors interfere with the action of alpha-amylase. By blocking the breakdown of starch, they reduce the absorption of starch calories. However, high amounts of amylase inhibitors may also cause diarrhea due to the effects of undigested starch in the colon.